Hundreds of publications have shown the importance of CART peptides. They modulate drugs of abuse, regulate food intake and have other physiologic roles. In order for CART peptides to carry out these functions, they must be regulated. In other words, the levels of the peptides must be able to change fairly rapidly in order to respond to their needs and demands. Indeed, it has been shown that CART levels do change quickly (in hours) in response to cocaine and amphetamine and food deprivation, for example. This project will study how CART levels change, or in other words, the mechanisms accounting for the changes. This is essential knowledge for a full understanding of these important peptides. This work will focus on CART in drug abuse, and on the regulation of the CART expression by cell signaling and by control of the promoter of the CART gene. Many of the experiments will be carried out in brain which is the most relevant tissue for the functions considered. More specifically, much work will study CART expression and regulation in the nucleus accumbens which is a key center for understanding drug addiction. It is expected that a critical role for CREB, a known regulator in drug addiction, will be established for CART regulation. In addition, other molecules like CREB transcription factors, will be identified that also play a role in regulating CART. Finally, the role of calcium, an important intracellular regulator will be shown to regulate CART as well. All of these regulatory factors act together and integrate in the intact animal and the behavioral effects of some experimental changes will be examined as well. It is expected that altering CART regulation will in turn alter the effects of some drugs such as cocaine, for example. Understanding how CART levels are controlled may lead to new strategies to develop medications that affect the CART system. Such medications could very well be helpful for public health problems such as drug addiction and obesity.